Using modified intention-to-treat as a principal stratum estimator for failure to initiate treatment

TL;DR

This paper clarifies that modified intention-to-treat (mITT) analysis estimates a principal stratum effect, and under certain assumptions, it can be unbiased for the subgroup of participants who would initiate treatment regardless of assignment.

Contribution

It demonstrates that mITT estimates a principal stratum estimand and provides criteria to assess when this approach is unbiased, clarifying its interpretability in clinical trials.

Findings

mITT estimates a principal stratum effect in certain conditions

Unbiasedness of mITT depends on measurement and assumption validity

Most double-blind trials satisfy the criteria for unbiased mITT estimation

Abstract

Background: A common intercurrent event affecting many trials is when some participants do not begin their assigned treatment. Many trials use a modified intention-to-treat (mITT) approach, whereby participants who do not initiate treatment are excluded from the analysis. However, it is not clear the estimand being targeted by such an approach or the assumptions necessary for it to be unbiased. Methods: We demonstrate that a mITT analysis which excludes participants who do not begin treatment is estimating a principal stratum estimand (i.e. the treatment effect in the subpopulation of participants who would begin treatment, regardless of which arm they were assigned to). The mITT estimator is unbiased for the principal stratum estimand under the assumption that the intercurrent event is not affected by the assigned treatment arm, that is, participants who initiate treatment in one arm would also do so in the other arm. Results: We identify two key criteria in determining whether the mITT estimator is likely to be unbiased: first, we must be able to measure the participants in each treatment arm who experience the intercurrent event, and second, the assumption that treatment allocation will not affect whether the participant begins treatment must be reasonable. Most double-blind trials will satisfy these criteria, and we provide an example of an open-label trial where these criteria are likely to be satisfied as well. Conclusions: A modified intention-to-treat analysis which excludes participants who do not begin treatment can be an unbiased estimator for the principal stratum estimand. Our framework can help identify when the assumptions for unbiasedness are likely to hold, and thus whether modified intention-to-treat is appropriate or not.